Specific association of the gene product of PKD2 with the TRPC1 channel

The function(s) of the genes (PKD1 and PKD2) responsible for the majority o f cases of autosomal dominant polycystic kidney disease is unknown. While P KD1 encodes a large integral membrane protein containing several structural motifs found in known proteins involved in cell-cell or cell-matrix intera ctions, PKD2 has homology to PKD1 and the major subunit of the voltage-acti vated Ca2+ channels. We now describe sequence homology between PKD2 and var ious members of the mammalian transient receptor potential channel (TRPC) p roteins, thought to be activated by G protein-coupled receptor activation a nd/or depletion of internal Ca2+ stores. We show that PKD2 can directly ass ociate with TRPC1 but not TRPC3 in transfected cells and in vitro. This ass ociation is mediated by two distinct domains in PKD2, One domain involves a minimal region of 73 amino acids in the C-terminal cytoplasmic tail of PKD 2 shown previously to constitute an interacting domain with PKD1, However, distinct residues within this region mediate specific interactions with TRP C1 or PKD1. The C-terminal domain is sufficient but not necessary for the P KD2-TRPC1 association. A more N-terminal domain located within transmembran e segments S2 and S5, including a putative pore helical region between S5 a nd S6, is also responsible for the association. Given the ability of the TR PC to form functional homo- and heteromultimeric complexes, these data prov ide evidence that PKD2 may be functionally related to TRPC proteins and sug gest a possible role of PKD2 in modulating Ca2+ entry in response to G prot ein-coupled receptor activation and/or store depletion.